Natural and synthetic flavonoid derivatives as new

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Natural and synt

EWadUioUsKtPm

the group of Prof. Dr Xinliang Fenpendent research group at theUniversity of Gujrat, Gujrat, Pakisests focus on the design and syntsynthetic avonoids, transitiocomplexes and their fabrication incarbon-rich polycyclic aromatic corganic electronics.

Cite this: RSC Adv., 2021, 11, 22159

Received 24th April 2021Accepted 31st May 2021

DOI: 10.1039/d1ra03196a

rsc.li/rsc-advances

aDepartment of Chemistry, Faculty of Appl

Makkah 21955, Saudi Arabia. E-mail: saahmbDepartment of Chemistry, University of G

[email protected] of Chemistry, Govt. College WomdDepartment of Pharmaceutical Chemistry, P

Taif, Saudi Arabia

© 2021 The Author(s). Published by

hetic flavonoid derivatives as newpotential tyrosinase inhibitors: a systematic review

Rami J. Obaid,a Ehsan Ullah Mughal, *b Nafeesa Naeem,b Amina Sadiq,c

Reem I. Alsantali,d Rabab S. Jassas,e Ziad Moussa f and Saleh A. Ahmed*agh

Tyrosinase is a multifunctional glycosylated and copper-containing oxidase that is highly prevalent in plants

and animals and plays a pivotal role in catalyzing the two key steps of melanogenesis: tyrosine's

hydroxylation to dihydroxyphenylalanine (DOPA), and oxidation of the latter species to dopaquinone.

Melanin guards against the destructive effects of ultraviolet radiation which is known to produce

considerable pathological disorders such as skin cancer, among others. Moreover, the overproduction of

melanin can create aesthetic problems along with serious disorders linked to hyperpigmented spots or

patches on skin. Several skin-whitening products which reduce melanogenesis activity and alleviate

hyperpigmentation are commercially available. A few of them, particularly those obtained from natural

sources and that incorporate a phenolic scaffold, have been exploited in the cosmetic industry. In this

context, synthetic tyrosinase inhibitors (TIs) with elevated efficacy and fewer side effects are direly

needed in the pharmaceutical and cosmetic industries owing to their protective effect against

pigmentation and dermatological disorders. Furthermore, the biological significance of the chromone

hsan Ullah Mughal was born inazirabad, Pakistan in 1978nd obtained his master'segree from Quaid-e-Azamniversity, Islamabad, Pakistann organic chemistry. In 2013, hebtained his PhD from Bielefeldniversity, Germany under theupervision of Prof. Dr Dietmaruck. Thereaer, he moved tohe Max Planck Institute forolymer Research, Mainz, Ger-any for a postdoctoral stay ing. In 2015, he started his inde-Department of Chemistry intan. His current research inter-hesis of bioactive heterocycles,n metals-based terpyridinedye-sensitized solar cells and

ompounds for applications in

Saleh Abdel-Mgeed Ahmed wasborn in Assiut, Egypt in 1968and received his bachelor's andmaster's degrees from AssiutUniversity, Egypt, and PhD inphotochemistry (photochro-mism) under the supervision ofProf. Heinz Durr in SaarlandUniversity, Saarbrucken, Ger-many as DAAD fellow. Duringhis last 27 years of stay inEurope, Japan, and the USA, hehad successfully published more

than 190 publications and has more than 15 registered and ledpatents in the US patent office. His current research interestsinclude synthesis and photophysical properties of novel organiccompounds such as material-based gels, electronic devices, solarenergy conversion, and bioactive materials.

ied Sciences, Umm Al-Qura University,

[email protected]

ujrat, Gujrat-50700, Pakistan. E-mail:

en University, Sialkot-51300, Pakistan

harmacy College, Taif University, 888-

eDepartment of Chemistry, Jamoum University College, Umm Al-Qura University,

21955 Makkah, Saudi ArabiafDepartment of Chemistry, College of Science, United Arab Emirates University, P. O.

Box 15551, Al Ain, Abu Dhabi, United Arab EmiratesgResearch Laboratories Unit, Faculty of Applied Science, Umm Al-Qura University,

21955 Makkah, Saudi ArabiahDepartment of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt

the Royal Society of Chemistry RSC Adv., 2021, 11, 22159–22198 | 22159

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https://doi.org/10.1039/d1ra03196a

https://pubs.rsc.org/en/journals/journal/RA

https://pubs.rsc.org/en/journals/journal/RA?issueid=RA011036

22160 | RSC Adv., 2021, 11, 22159–22

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skeleton and its associated medicinal and bioactive properties has drawn immense interest and inspired

many researchers to design and develop novel anti-tyrosinase agents based on the flavonoid core (2-

arylchromone). This review article is oriented to provide an insight and a deeper understanding of the

tyrosinase inhibitory activity of an array of natural and bioinspired phenolic compounds with special

emphasis on flavonoids to demonstrate how the position of ring substituents and their interaction with

tyrosinase could be correlated with their effectiveness or lack thereof against inhibiting the enzyme.

1. Introduction

Tyrosinase (E.C. 1.14.18.1) is a multifunctional copper-containing oxidase enzyme1,2 and is biologically signicantbecause of the key role it plays in the biosynthesis of melaninpigment in living organisms.3–6 It catalyzes the o-hydroxylation ofpolyphenolic substrates to diphenol (catechol) derivatives, whichfurther oxidize to o-quinone products.7 Tyrosinase is known asa rate-limiting enzyme that catalyzes the hydroxylation of L-tyrosineto L-DOPA and 3,4-dihydroxyphenylalanine to dopaquinones whichcan cause unusualmelanin pigment accumulation in the outermostlayer of the skin.8 In this context, the standard tyrosinase inhibitors(TIs) such as kojic acid, tropolone, hydroquinone and mercury areclinically effective andmay function asmedicines for facial aesthetictreatments and other more serious dermatological disorders relatedto melanin hyperpigmentation in human skin. In addition, they areused in-cosmetics as skin-whitening agents and in agriculture asbio-insecticides.9–12 These inhibitors typically work by chelating withCu2+ cation in the active site of tyrosinase or replacing it, as in thecase of mercury, thus inhibiting the substrate–enzyme interactionand disrupting the ensuing electrochemical oxidation process. Overthe past decade, a number of naturally occurring and synthetic TI'shave been reported,13–15 though most of these inhibitors have asso-ciated toxic effects and low efficacy problems. In addition toproviding pigmentation necessary for photoprotection, tyrosinase isalso responsible for a variety of biological processes in arthropodsincluding wound healing, cuticle sclerotization, and protectiveencapsulation. In plants, it is responsible for promoting enzymaticbrowning processes in damaged crops following harvest handlingand managing. Thus, the production of efficient and harmless TI'sis therefore essential not only for insect control, but also for use inthe cosmetic, food, medical and agricultural industries.16

Despite extensive efforts to design and synthesize TI's, suchcompounds are scant and only few (e.g., PTU, anthracene, tro-polone, and arbutin) have been employed in cosmetics and astherapeutic agents.17–21 However, because of poor safety proles,adverse effects, or low efficacy, only a handful of them have beencontinued and put into practice.22–29 Undoubtedly, now morethan ever, there is an urgent need to identify and develop moreefficient and safer tyrosinase inhibitors.

1.1 The role of tyrosinase enzyme in the biosynthesis ofmelanin pigment

Melanin is the essential pigment formed by the dermal cellsin the deepest layer of the epidermis known as the basal layer.It is produced by specialized cells called melanocytes througha multi-step chemical process where the amino acid tyrosineis oxidized, followed by polymerization. Melanogenesis isinitiated in the skin following exposure to UV radiation and is

198

able to dissipate almost completely the absorbed UV radia-tion. Thus, melanin performs an essential role in shieldingthe skin from the detrimental impacts of the sun's ultravioletrays.30–32 Even though melanin primarily exhibits a photo-protective role in human skin, the accretion of melanin invarious parts of the skin results in more pigmented spots andpatches that could become an aesthetic problem.33,34 In worstcases, frequent exposure to UV radiation may be associated withincreased risk of a cancer of melanocytes know as malignantmelanoma. Furthermore, the enzymatic browning on the slicedsurface of fresh fruits and vegetables can reduce the shelf life andimpact their quality.35,36 Melanogenesis is the mechanism thatleads to the development of dark molecular stains, i.e., melanin.When the skin is exposed to frequent and excessive UV radiation,abnormal melanin pigment formation occurs, creating severeaesthetic deformity especially common among elderly andmiddle-aged people. The biosynthesis of melanin can also be triggered byfree radicals. As a countermeasure, antioxidants that can detoxifyfree radicals prevent oversupply of melanin. Few examples ofantioxidants used as melanogenesis inhibitors include vitamin Cand reduced glutathione. The benet of developing tyrosinasechemistry is expected to provide deeper understanding of how toincreased shelf life of products and efficiently increase farmingyields while simultaneously minimizing economic loss.37–41

As stated earlier, melanocytes are cells produced in thedermal basal layer and are important in melanogenesis, theprocess of biosynthesizing melanin. Melanocytes are melano-blasts formed-dendritic cells that are unpigmented cells origi-nating from neural crest cells of the embryos. These are mainlyinvolved in melanin pigment synthesis. Each melanocyte issurrounded by about 36 keratinocytes which are the primarytype of cell present in the outermost layer of the skin. Aersynthesizing melanin, it is stored inside melanosomes andsubsequently transferred, using extended dendrites, to theoutermost layer of suprabasal keratinocytes.42 Fig. 1 shows thatskin pigmentation is caused by keratinocyte cornication whichincludes the mature melanosomes which are biosynthesized,used to store melanin and transferred by the melanocytes to thekeratinocytes. Eventually, keratinocytes undergo a process ofcornication or programmed cell death andmigrate, along withthe engulfed melanin, to the skin surface. Cornication formsthe outermost skin barrier known as the cornied layer.

With tyrosinase being the main enzyme that boosts up theprocess of melanin formation, tyrosinase inhibitors representkey inhibitory agents to combat the excess production ofmelanin. On the other hand, since the biosynthesis of melanincan also be triggered by free radicals, various natural andsynthetic antioxidant systems able to scavenge such radicalsmay control excess production of melanin.43–46

© 2021 The Author(s). Published by the Royal Society of Chemistry




Fig. 1 Mechanism of skin pigmentation.

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2. Properties of various kinds oftyrosinase2.1 Properties of mushroom tyrosinase

Tyrosinases have been extracted and rened from a variety ofnatural sources including some herbs, animals, and microbes.Although in many cases the isolated enzymes were sequenced,especially those extracted from humans, very few were properlycharacterized or probed. Recently, a new tyrosinase produced bySahara soil actinobacteria was isolated and chemically charac-terized to detect novel enzymes useful for biotechnologicalpurposes. Heretofore, among the various sources of tyrosinase,the Agaricus bisporus mushroom is the most common andinexpensive tyrosinase source where the enzyme exhibits highlevel of structural resemblance and homology to the humantyrosinase. Tyrosinase, a 120 kDa tetramer with two isolatedintense and light subunits, was isolated from Agaricus bisporusby Bourquelot and Bertrand in 1895. It binds to six histidineresidues and has three domains and two copper-binding sitesthat interact with molecular oxygen in the tyrosinase active site.Additionally, its structure is stabilized by the presence ofdisulde linkage. Recently, a 50 kDa Agaricus bisporus (H-subunit) tyrosinase isoform with a high specic activity ofover 38 000 U per mg has been identied and puried.47–52a

Fig. 2 Catalytic cycle for the hydroxylation of monophenol and theconversion of o-diphenol to o-quinone by the tree types of tyrosinase,Eoxy, Emet, and Edeoxy.24

2.2 Properties of mammalian tyrosinase

Tyrosinases found in different living species are oen very diverse interms of chemical structure, structural properties, distribution invarious tissues, and cellular location. The mammalian tyrosinase is


characterized as single membrane-spanning transmembrane pro-tein.52b In humans, this enzyme is sorted into organelles know asmelanosomes52c and the catalytically active site of the protein issituated within melanosomes. Notably, only a short, enzymaticallysuperuous part of the protein extends into the cytoplasm of the

RSC Adv., 2021, 11, 22159–22198 | 22161




Fig. 3 Molecular mechanism of tyrosinase suicide deactivation by oxidation of an o-diphenol substrate. The curly arrows showed thatdeprotonation results in the reduction of copper from bivalent to zero-valent form, and the elimination of an o-quinone and tyrosinaseinactivation.62

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melanocyte. Among the different known types of tyrosinases, themushroom tyrosinase is known to exhibit the highest homologywith mammalian tyrosinase and is the only commercially availableenzyme andmay be purchased through several chemical vendors.52d

Fig. 4 Comparative SAR study of the most potent subclass (flavonol) aincreased activity and the red arrow indicates decreased activity.

22162 | RSC Adv., 2021, 11, 22159–22198

2.3 Properties and signicance of human tyrosinase

In humans, melanin is biosynthesized in melanosomes, whichare organelles located inside melanocytes in skin and hair, andretinal pigment epithelium cells in the eye.52e Three tyrosinase-

mong flavonoids with standard kojic acid. The green arrow indicates





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like enzymes are involved in its biosynthesis, tyrosinase (TYR)and tyrosinase-related proteins 1 and 2 (TYRP1 and TYRP2).Recent developments on the structure of TYR and TYRPs andtheir function by virtue of the crystal structure of human TYRP1,which represents the rst available structure of a mammalianmelanogenic protein have been reviewed by X. Lai et al.52f

Combining the preceding structure with those found for tyros-inases from other lower eukaryotes and mutagenesis studies ofcatalytically active domains, have provided deeper insight intothe mechanism of action of TYR and TYRPs proteins. In addi-tion, a TYRP1-based homology model of TYR has now given thenecessary foundation to gene map and investigate mutationsassociated with albinism, as well as to design specic anti-melanogenic agents. Mutations in the TYR or TYRP1 genesleads to oculocutaneous albinism (OCA1 and OCA3, respec-tively), a group of autosomal recessive conditions involvingunderproduction of melanin in skin, hair and eyes. Further,

Table 1 Structures of some mushroom tyrosinase inhibitors36

Compound name Compound structure Source

Arbutin Extrac

Tropolone Isolate

Kojic acid Obtain

Cuminaldehyde Obtain

Oxyresveratrol Obtain

Cupferron Obtain

p-Coumaric acid Obtain


TYR and TYRP1 variants are closely associated with the devel-opment of melanoma, a malignant tumor of melanocytesresponsible for the majority skin cancer related deaths.52g Onthe other hand, overproduction of melanin or abnormaldistribution may lead to pigmentation disorders, such as over-tanning, age spots and melasma,52g which has triggered thedevelopment of skin-whitening products to lower the melanincontent. Nowadays, inhibition of melanin biosynthesis is beingconsidered as a rational therapeutic strategy to treat advancedmelanotic melanomas.52h

2.4 Reaction mechanism of tyrosinase

The catalytic cycle of tyrosinase involves two steps as shown inFig. 2. First, monophenols are hydroxylated to o-diphenols bya monophenolase activity, and diphenols are hydroxylated bya diphenolase activity. In the second step, tyrosinase oxidizes o-

ted from the dried leaves of bearberry plant in the genus Arctostaphylos

d from Pseudomonas lindbergii

ed from a few species of Aspergillus

ed from essential oils

ed from the extract of heartwood

ed from natural samples rich in organic matter

ed from pollens

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diphenols to o-quinones. There exist a variety of chemicalreactions that are coupled simultaneously to the enzymaticreaction in which two o-dopaquinone molecules react with eachother to produce an o-diphenol fragment and a dopachromeparticle (Fig. 2). Later on, when the tyrosinase molecule reactswith an o-diphenol, it is possible to investigate diphenolasebehavior on its own. They form met-tyrosinase that furtherlyjoins the o-diphenol activating the complex EmD. This complexthen oxidizes the o-diphenols into o-quinone and subsequentlythe enzyme is transformed into the deoxytyrosinase form. Edexhibits high affinity for O2, initiating the oxy-tyrosinase form,which furtherly attaches to another o-diphenol fragment,forming a new multifaceted EoxD complex.

Later, o-diphenol is oxidized once more to o-quinone and Em

is formed, completing the catalytic cycle. Following theseenzymatic reactions, two o-quinone molecules react together,producing dopachrome and regenerating an o-diphenol

Fig. 5 General structure of flavonoids and relevant pharmacophoric str

Scheme 1 Synthesis of some flavonoids from substituted 20-hydroxycha

22164 | RSC Adv., 2021, 11, 22159–22198

molecule. Although diphenolase activity may be reviewedindependently, this is not valid for monophenolase activitybecause chemical reactions of diphenolase andmonophenolaseproduction take place simultaneously. Furthermore, themonophenolase activity is expressed by tyrosinase in a giventime interval. There are two new complexes formed by mono-phenolase activity. One is EoxM and the second one is EmM.EoxM is an active form and converts into EmD, which isprimarily an intermediate in the catalytic cycle. The o-quinonesproducts thus formed by these two oxidation cycles can reactspontaneously with one another to form oligomers.24,53–56

3. Tyrosinase inhibition

Owing to the essential function of tyrosinase in the tanningprocess and melanogenesis, many studies describing theidentication of TI's from both biological and synthetic sources

uctural features.

lcone.





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have been reported. Typically, the activity of TIs is estimated inthe presence of a tyrosine or L-dopa substrate, and the activity isevaluated based on dopachrome formation.57–61

3.1 Tyrosinase inhibition mechanism

Different classes of compounds can prevent melanogenesis, forexample, unique TI's and inactivators, different enzymaticsubstrates, dopaquinone foragers, non-specic enzyme denatur-ants, and nonspecic enzyme inactivators attach to the enzymeand hinder its process. Suicide inactivators were commonlyregistered for the treatment of hyperpigmentation. To describetyrosinase suicide deactivation (Fig. 3), two pathways have beenproposed. In the rst pathway, it has been suggested that theconformational changes initiated by the inhibitor's complex in the

Fig. 6 Representative anti-tyrosinase scaffolds.

Fig. 7 Various sub-classes of flavonoids.89


3D structures of tyrosinase may rationalize the suicide deactiva-tion. Conversely, in the second pathway, suicide deactivation maytake place following the proton transfer to the peroxyl bridge onthe oxy-tyrosinase active site.62

Moreover, to determine the inhibitory mechanism, the IC50

value could be premeditated in the kinetics studies of enzymeand inhibitor's screening to compare the inhibitory strength ofan inhibitor with that of a standard and other inhibitors.Though the inhibitory values can be incomparable owing todifferent assay conditions (various substratum developmenttime, concentrations, and numerous tyrosinase sources),a positive standard could be used for this purpose to normalizevalues.63,64 Unfortunately, many researchers have not deter-mined IC50 values of novel TIs nor applied positive standards in

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Table 2 Chemical structures of natural anthocyanidins and IC50 values against mushroom tyrosinase

Compound no. Compound name Chemical structures IC50 values (mM) Reference

1 Malvidin 45 31

2 Peonidin 22 31

3 Pelargonidin 78 31

4 Haginin A 5.0 31

5 Delphinidin 20.9 31

64-(8,8-Dimethyl-2H,8H-pyrano[2,3-f]chromen-3-yl)benzene-1,3-diol

0.09 31

7 Cyanidin-3-O-glucoside 18.1 140

22166 | RSC Adv., 2021, 11, 22159–22198 © 2021 The Author(s). Published by the Royal Society of Chemistry

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Table 2 (Contd. )


8 Delphinidin-3-O-glucoside 7.5 31

Standard Kojic acid 59.3 31 and 140

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their research like kojic acid, hydroquinone and arbutin whichare typically used as a standards. Though amongst variouskinds of TI's, few inhibitors such as azelaic acid, kojic acid,tranexamic acid, ellagic acid and L-ascorbic acid have beenidentied in cosmetic products as skin-whitening agents.Despite the good safety prole of these drugs, several studiesfailed to prove their outcome as useful skin lightening agents inclinical trials.65–67

From a structural point of view, the two divalent copper ionsthat are surrounded by three histidine residues are responsiblefor the catalytic activity of tyrosinase. A docking study (in silico)revealed that the various TIs expressed their inhibitory potentialthrough hydrophobic p-alkyl, hydrophobic p–s, hydrophobicp–p T-shaped, and hydrophobic p–p stacked type interactionswith His263, Phe264, Ala286, Val283, and His85 amino acidresidues inside of the activation loop of targeted tyrosinasebiological molecule.52d

Aer an extensive structure–activity relationship studies, the SARdata suggest that among all the avonoid derivatives, the avonolclass stands out and offers themost potent inhibitory activity due toits structural resemblance with that of the standard inhibitor kojicacid. In particular, the phenyl-g-benzopyran core structure playsa vital role in tyrosinase inhibitory activity. It is noted though thatvariation in the activity of these inhibitors is attributed to variabilityin the positions and nature of substituents on the aryl ring (B) aswell as the nature of ring B. Introducing halogen atoms into ring Aof 2-phenylchromones enhances the electron density along with thehydrophobicity of the molecules and fosters strong bonding inter-actions. The structure of such inhibitors is therefore customizableand may be tuned to achieve optimum potency. The aforemen-tioned results suggest that 3-hydroxyavone molecules can serve asfascinating candidates for the treatment of tyrosinase-related


ailments and as lead compounds for the development of potentnew tyrosinase inhibitors (Fig. 4).

4. Natural and synthetic sources ofinhibitors4.1 Natural phenolic tyrosinase inhibitors and their sources

Living organisms have developed shielding mechanisms tosafeguard against the destructive actions of UV radiations.Hence, nature has a multitude of tyrosinase inhibitor sources.Several investigators have described the isolation of tyrosinaseinhibitors from mycological metabolites, plants, and aquaticalgae, among other sources. Tyrosinase inhibitors from naturalresources commonly attract more interest compared tosynthetic ones to meet cosmetic demand and requirements.The IC50 values for the current TI's in the literature areincomparable because of the differences in assay conditions,such as substrate concentration, different time of incubation,and various lots of tyrosinases (Table 1). Henceforth, manyresearchers have been using the most recognized TI, forexample, kojic acid as a standard to adjust and normalize thereported inhibitory activity values.68–72

4.2 Synthetic phenolic tyrosinase inhibitors

In recent years, numerous studies have addressed the devel-opment of new TI's based on natural structural motifs, yetdesigned to overcome issues related to chemical stability,effectiveness, and isolated yield.9,73 Thus, bioinspired by thevarious structural scaffolds of natural tyrosinase and the exist-ing research course to design useful synthetic compounds(Fig. 5), synthetic inhibitors with new structural moieties as wellas analogs of natural compounds have been synthesized(Scheme 1).74,75

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Table 3 Chemical structures of natural aurones and IC50 values against mushroom tyrosinase


9 4,6,40-Trihydroxyaurone 38 35

10 Altilisin J 98.5 107

11 Aurone 12.3 31

12 Altilisin H 85 107

137-Hydroxy-2-(4-hydroxybenzylidene)benzofuran-3(2H)-one

31.7 106

145-Hydroxy-2-(4-hydroxybenzylidene)benzofuran-3(2H)-one

38.4 106


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Table 3 (Contd. )


15 Altilisin I 88.9 107

16 2-Hydroxypyridine N-oxide aurone 1.5 111

Standard Kojic acid 167107 and111

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Various potent or weak synthetic (Scheme 1) and naturalinhibitors have been reported for tyrosinase.76–78 Flavonoids, themost abundant and commonly studied polyphenols, are benzo-g-pyrones comprising of pyrene and phenolic rings (Fig. 5). Broadlyspread in the owers, seeds, barks, and leaves, more than 4000avonoids have been discovered up to date. Flavonoids areaccountable for the distinguished blue and red colors of wines,berries, and a variety of vegetables. Flavonoids can be divided intoeight different classes, including aurones, chalcones, avonols,avones, avanols, avanones, and anthocyanins. Various avo-noid classes are characterized by oxygen-containing ve or six-membered heterocyclic rings, and by variation in the position ofring B, and by –OH, –CH3, and –OCH3 groups widely spread invarious distinct patterns around the rings.79–81 Besides avonoids,other polyphenols, which are also known as TIs, include coumarinand stilbenes derivatives (Fig. 6).82 Detailed investigations haveproven that few avonoids are very powerful and effective inhibi-tors and are discussed in this segment.83–86

5. Flavonoids

Flavonoids belong to a class of naturally occurring plantpolyphenolic secondary metabolites that are broadlydispersed in the plant kingdom and therefore commonlyconsumed in diet. Generally, they are identied as compoundshaving the C6–C3–C6 carbon framework as a core structure con-sisting of 15-carbon atoms. These oen comprise two phenyl rings,


designated as A and B, and a heterocyclic ring. Biological studiesperformed on natural and synthetic analogs of avonoids haveuncovered a considerably broad range of bioactivities manifestedby these species which include anxiolytic, anti-microbial, anti-cancer, anti-inammatory, anti-ulcer, and thrombosis.85,87–90

Certain avonoids commonly found in herbs, vegetables, orobtained from synthetic routes, have shown promising prospects aspotential TIs among polyphenolic compounds. There is a consider-able connection and correlation between the avonoid's inhibitorypotency on tyrosinase and melanin formation in melanocytes.

Several avonoids, extracted from biological resources suchas Teretrius nigrescens, Myristica yunnanensis, Pleurotus ostrea-tus, roots of Morus lhou, and Palhinhaea cernua, herbal plants,and other numerous medicinal plants, were analyzed for theirinhibitory action on tyrosinase in the search for effectiveTI's.91–94 Flavonoids are categorized into various classes, forinstance, isoavones, avonols, avanonols, avanones, avan-3,4-diols, anthocyanidins, avones, aurones, and chalcones(Fig. 7). Other avonoid subclasses include vinylated and acet-ylated avonoids, as well as their glycosides. Few avonoidglycosides such as myricetin galactoside and quercetin gal-actopyronaside from Epilobium tetragonum have been examinedfor their TI activities. Remarkably, it has been revealed that farIR irradiation can increase the TI activity of certain avonoidglycosides.95–103 In a review of recent ndings, Orhan et al.surveyed many tyrosinase inhibitors incorporating the avo-noid scaffold.104 Many promising TI's from different classes of

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Table 4 Chemical structures of synthetic aurones and IC50 values against mushroom tyrosinase


17 2-(2,4-Dihydroxybenzylidene)-5-hydroxybenzofuran-3(2H)-one >1000 106

18 2-(2,4-Dihydroxybenzylidene)-6-hydroxybenzofuran-3(2H)-one >1000 106

19 4-Hydroxy-2-(4-hydroxybenzylidene)benzofuran-3(2H)-one 31.7 31

202-(2,4-Dihydroxybenzylidene)-4,6-dihydroxybenzofuran-3(2H)-one

300 106

21 4,6-Dihydroxy-2-(4-hydroxybenzylidene)benzofuran-3(2H)-one 38.0 111

22 6-Hydroxy-2-(4-hydroxybenzylidene)benzofuran-3(2H)-one 38.4 31


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Table 4 (Contd. )


23 2-(2,4-Dihydroxybenzylidene)-4-hydroxybenzofuran-3(2H)-one 9 106

Standard Kojic acid 280 31, 106 111

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natural and synthetic avonoids have been summarized and therole of avonoids has been highlighted and recommended asthe focus of future and continued tyrosinase inhibition studies.

5.1 Anthocyanidins

Anthocyanin, also known as common sugar-coupled anthocya-nidin, is a avonoid found in plants and is accountable for thebright color of vegetables and fruits. It has wound healing andantioxidant properties. Anthocyanin is a naturally occurringpigment that can lessen excess free radicals in the body and candecrease the risk of cancer and cardiovascular diseases.Hibiscussabdariffa Linn., an annual herbaceous shrub, is an exceptionalresource of anthocyanin. Toxicity reports indicated that antho-cyanin from Hibiscus sabdariffa can shield rat liver from thepoisoning and destructive effect of tert-butyl hydroperoxide dueto the antioxidant action of the former species. Still, there is noevidence that anthocyanin from Hibiscus sabdariffa inhibitsmelanogenesis. However, compounds 4, 6, and 8 (IC50 ¼ 5, 0.09,and 7.5 mM) in Table 2 have shown excellent tyrosinase inhib-itory activities.

Anthocyanin molecules are highly unstable and prone todegradation because they are charged. The anthocyanin colorpersistency is inuenced by temperature, presence of enzymes,pH, light, concentration, structure of the anthocyanin, and theexistence of complex derivatives such as other phenolic acids,avonoids, and metals. Anthocyanin has excellent antioxidantimpacts but is susceptible to the effect of biological factors.Hence, encapsulating anthocyanin in liposomes will effectivelyextend the half-life of anthocyanin (Table 2).105 At the momentand to the best of our knowledge, there is no literature availableon synthetic anthocyanins as mushroom TIs.

5.2 Aurones

Aurone itself is a weak inhibitor of the tyrosinase enzyme, but itssynthetic derivatives that contain more than two –OH groupsresiding at the 40, 4, and 6 positions are more potent TI's.Researchers found that natural aurones are most effective against


human tyrosinase. Synthetic aurone derivatives like 2-benzylide-nebenzofuran-3(2H)-ones and 20,30-dihydro-20-(1-hydroxy-1-meth-ylethyl)-2,60-dibenzofuran-6,40-diol are also important TI's.106

Aurones, natural as well as their synthetic analogs, showa broad array of bioactivities such as antimicrobial, anti-leishmanial, and anticancer. However, these natural biologi-cally active analogs are also specied for their inhibitory actionagainst many kinds of proteins and enzymes. Particularly,natural 4,6,40-trihydroxyaurone has been recognized as a highlyeffective inhibitor against human melanocyte-tyrosinase asshown in Table 3. In contrast with the known standard kojicacid, an excellent inhibitor of mushroom tyrosinase, 4,6,40-tri-hydroxyaurone showed even superior inhibitory results.107,108

Aurone and its derivatives were discovered as human tyros-inase inhibitors by Okombi et al.Moreover, they recognized thataurones themselves are weak blockers, yet their analogs withmore than three –OH groups, usually at the 40, 4, and 6 posi-tions, are potent TI's. For example, the most active aurone,compound 9 (Table 3), causes 75% inhibition at 0.1 mMconcentration and is very efficient compared to the standardkojic acid.108

N. T. Mai and his colleagues (2012) have reported three newaurones (compounds 10, 12, and 15) isolated from a plant,Artocarpus altilis (Moraceae), which is broadly distributed overthe tropical regions of Asia.109 The isolated compounds weretested for their tyrosinase inhibitory activity (Table 3). The assaywas carried out at ve different concentrations ranging from 1to 100 mM for tyrosinase inhibition. All compounds possessedtyrosinase inhibitory activity with IC50 values less than 100 mM.Among them, compounds 12 and 15 showed more potentactivities with IC50 values of 85 mM and 88.9 mM, respectively.The results showed that these derivatives had an excellenttyrosinase inhibitory activity.

Dubois et.al. (2012) showed that the most potent auroneswere those bearing a –OH group at the 40-position of ring B.Believing that aurones interact with the binuclear Cu2+ activesite through this ring, they surveyed aurones in which the

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Table 5 Chemical structures of natural chalcones and IC50 values obtained against mushroom tyrosinase

Compoundno. Compound name Chemical structures IC50 values (mM) Reference

242,4,20,40-Tetrahydroxy-3-(3-methyl-2-butenyl)-chalcone (TMBC)

0.95 118

25 2,20,4,40-Tetrahydroxychalcone 0.07 113

26 Isoliquiritigenin 4.85 36

27 Kuwanon J 0.17 36

28 Kuraridin 0.6 27

29 Isobavachromene 15.8 134

30 Morachalcone A 0.14 112

31 40-O-Methylbavachalcone 48.8 134


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Table 5 (Contd. )


324'-(p-Toluenesulfonylamino)-4-hydroxychalcone

23.3 36

33 Isovabachalcone 12.3 134

34 Artocarmitin C 20.6 135

35 Flavokawain B 14.38 29

36 Flavokawain A 14.26 29

37 Xanthohumol 15.4 30

38 40-O-Methylxanthohumol 34.3 134

39 Xanthohumol C 41.3 30

40 Xanthoumol B 46.7 30

© 2021 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2021, 11, 22159–22198 | 22173

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Table 5 (Contd. )


41 Flavokawain C 106.7 29

Standard Kojic acid 89.529, 30, 134and 135

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position of the –OH group on the A ring is xed in the 6th

position. Compound 16 (IC50 ¼ 1.5 mM) was found to promote L-DOPA oxidation, which is mediated by tyrosinase. This partic-ular nding indicated that 2-benzylidenefuran can either act assubstrates or as hyperbolic activators.110

Among the synthesized aurone analogs, the one in which B-ring is substituted with a HOPNO group, compound 16 hasbeen determined as an efficient and novel mushroom tyrosi-nase inhibitor. The hybrid aurone 16 has been constructed bycombining an aurone moiety with 2-hydroxypyridine N-oxide,an excellent metal chelate.

In 2014, 24 different substituted hydroxylated aurones weresynthetically prepared by R. Haudecoeur and his coworkers toevaluate their repressing action towards bacterial and mush-room tyrosinases. The inhibitory behavior of the chemicalderivatives depended highly on the hydroxylation patterns ofrings A and B and the type of tyrosinase used. Among the newderivatives, 20,40-dihydroxyaurones were recognized as the besteffective mushroom and bacterial TI's. The presence of hydroxygroups in compounds 18, 19, and 22 at 4,40; 6,40; or 4,6,40

positions was found to be critical for excellent tyrosinaseinhibitory potencies in hydroxylated aurones. Based on theaforementioned ndings, compounds 18, 19, and 22 wereevaluated for their IC50 and proved much stronger and betterinhibitors (Table 4) than kojic acid (IC50 ¼ 280 mM) and arbutin(IC50 ¼ 8.4 mM).111

5.3 Chalcones

Chalcones are comprised of two trans-congured aryl rings,separated by 3C atoms, two of which are covalently bonded bya double bond (]) and the third is a carbonyl (C]O) func-tionality. Several natural acylated chalcones show potenttyrosinase inhibitory properties. Their aromatic rings aresubstituted with different functional groups: –OH, –OCH3, –R,and these substituents impact the bioactivities of chalcones.Several chalcones described in the literature show good tyrosi-nase inhibitory activity.8,58,112

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Khatib and colleagues discovered that mono-, di-, tri-, andtetra-substituted hydroxychalcones could inhibit tyrosinase.Compound 28 (Table 5), a prenylated chalcone isolated from theplant Sophora avescens, was highly potent as it exhibited 34fold activity compared to that of a standard against mushroomtyrosinase monophenolase. More intriguing, the two prenylatedchalcones also showed higher activity than their avanoneanalogs.27,96,97Kuraridin (a chalcone) was 10 timesmore active thankurarinone (a avanone). Compounds 28 and 24 produced 34- and26-fold TI activities than kojic acid, respectively (Table 5).

According to Nerya et al.,27 the location of the –OH groupsattached to the aryl rings A and B is the most essential structuralfeature required to produce strong tyrosinase inhibitory activityof chalcones, and there is a substantial preference for p-substituted ring B over substitution at ring A. However, thendings drawn from their recent study revealed conictingresults that chalcones with 2,4-DNPH and resorcinol moietiesdisplayed the greatest tyrosinase inhibitory activity, and theresorcinol subunit on ring B did not contribute effectively tomaximize TI action. In the presence of both Cu2+ ions andtyrosinase, the catechol on ring A acted like a metal chelator (inthe presence of Cu2+ ions) and a competitive inhibitor (in thepresence of tyrosinase), while the catechol on ring B underwentoxidation to the corresponding o-quinone. Compounds 24 and25 (IC50 ¼ 0.95 and 0.07 mM respectively) are powerful tyrosi-nase inhibitors.

Likewise, Jun et al.113 synthesized a chalcone series andanalyzed their tyrosinase repressive action. The ndings wereconsistent with their prior work,27 and themost active derivativereported was 2,4,20,40,60-pentahydroxychalcone, showing a 5-fold higher activity than 2,4,20,40-hydroxychalcone.

Nguyen et al.114 recently isolated acylated avones andchalcones from the wood of Artocarpus heterophyllus.Compound 30, which had a 3000-fold greater activity than kojicacid, was the most active of the isolated compounds withsignicant TI activity. Many synthetic derivatives of chalconeswere developed as effective candidates of tyrosinase





Table 6 Chemical structures of synthetic chalcones and IC50 values against mushroom tyrosinase


421-(2-Hydroxy-6-propoxyphenyl)-3-(4-(hydroxymethyl)phenyl)prop-2-en-1-one

26.8 96

433-(3-Amino-4-methoxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one

9.75 96

44 1,3-Bis(2,4-dihydroxyphenyl) prop-2-en-1-one 0.02 96

45 3-(4-Hydroxyphenyl)-1-phenyl prop-2-en-1-one 21.8 133

463-(2,4-Dihydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)prop-2-en-1-one

17.6 133


7.82 112

481-(2,4-Dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one

8.1 114

491-(2,4-Dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one

29.3 114

501-(1-(4-Methoxyphenyl)-3-phenylallylidene)thiosemicarbazide

0.274 123


9.75 112


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Table 6 (Contd. )


523-(2,4-Dihydroxyphenyl)-1-(3-hydroxynaphthalen-2-yl)prop-2-en-1-one

114.4 116

533-(3,5-Dihydroxyphenyl)-1-(3-hydroxynaphthalen-2-yl)prop-2-en-1-one

10.4 116

541-(3-Hydroxynaphthalen-2-yl)-3-(pyridin-3-yl)prop-2-en-1-one oxime

12.22 117

551-(3-Hydroxynaphthalen-2-yl)-3-(pyridin-4-yl)prop-2-en-1-one oxime

19.45 117

563-(4-(Dimethylamino) phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one

14.20 112

Standard Kojic acid 57.9112, 116, 123and 133

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inhibitors,115–117 inspired by their versatile bioactivity andunique structural motif. Some natural and synthetic chalcones, aswell as their derivatives, have been reported as new potent depig-menting agents and TI's, according to several studies (Table 6). Upto now, natural chalcone isoliquiritigenin from licorice roots,2,4,20,40-hydroxycalcone and three of its analogs with 30-substitutedresorcinol moieties from Malacosteus australis (Table 5) 2,4,20,40-tetrahydroxy-3-(3-methyl-2-butenyl)-chalcone from Morus nigra,2,4,20,40-tetrahydroxychalcone (IC50 ¼ 0.07 � 0.02 mM) and mor-achalcone A (IC50¼ 0.08� 0.02 mM) fromMorus alba L. have beendesignated as tyrosinase inhibitors.115

Tetrahydroxychalcone and its various derivatives (such asnaphthyl chalcones and their thiosemicarbazide) have beendescribed as a novel class of TI's (Table 6). Remarkably,compounds 44, 46, 50, and 54 have shown excellent tyrosinaseinhibitory activity due to the presence of –OH groups on rings A

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and B and the number of –OH groups, while the presence ofa catechol group did not correlate with rising tyrosinase inhi-bition potency.116,117

The synthesized chalcones, compound 47 and compound 51(Table 6) were proven to be the most potent TIs in a competitiveway. Their IC50 values indicated that they were more potent thankojic acid, the reference compound.27,118,119

Nerya et al. reported that chalcones are highly potent newdepigmenting agents, with their dual effect of antioxidantactivity and reductants.27,120 Tables 4 and 5 depict chalcone andits analogs showing anti-tyrosinase behaviors (IC50 values).121–123

5.4 Flavones

Flavone belongs to the class of avonoids having a 2-phenylchromen-4-one backbone. They can be found in someyellow and orange fruits and vegetables, as well as spices.





Table 7 Chemical structures of natural flavones and IC50 values obtained against mushroom tyrosinase


57 Baicalein 110 93

58 Luteolin 20.8 30

59 Norartocarpetin 1.2 86

60 Apigenin 17.3 30

61 Tangeretin 25 87

62 Nobelitin 29.8 124

63 6,7-Dihydroxy-2-phenyl-4H-chromen-4-one 2.8 30


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Table 7 (Contd. )


64 40,7,8-Trihydroxyavone 10.31 94

Standard Kojic acid 78 30, 86 and 94

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Apigenin, lutein, chrysin, and baicalein along with their glyco-sides, the polymethoxylated avones tangeretin, and nobiletin,are the most popular avones.86,87,124 Nguyen et al.114 havestudied the occurrence of compounds 60 and 62 from themethanolic extract of Artocarpus altilis with 11 other poly-phenolic derivatives for their TI activity.

Shang et al.93 discovered a avone derivative, namely 7,8,40-trihydroxyavone, which prevents tyrosinase diphenolaseaction (Table 7). The proposed binding mechanism involvedvan der Waals forces and hydrogen bonding, according to thethermodynamics parameters. In addition, docking simulationsrevealed H-bonding between this compound and the active siteresidues His244 and Met280. Several hydroxyavones, such as6-hydroxyapigenin, baicalein, and 6-hydroxykaempferol, and 6-hydroxygalangin have also been shown as inhibitors of tyrosi-nase diphenolase activity (Table 7). Another active avone,compound 57 (5,6,7-trihydroxyavone), has been obtained fromthe roots and aerial parts of Chrysanthemum morifolium andOroxylum indicum (Indian trumpet ower) (Table 7). Thecompound shows tyrosinase inhibition by inducing conforma-tional changes within the structure of the target enzyme.125,126

Nihong Guo et al. estimated the active site for bindinginteraction is present at the bottommost cavity of tyrosinase.From docking studies carried out using the same tyrosinaseenzyme (PDB: 2Y9X), intermolecular interaction conrmed thebinding between tyrosinase and baicalein which effectivelyproduced a docking score of �6.20 kcal mol�1 for bindingconformation. Several adjacent residues which include His85,Val 248, Phe264, Met280, Ser282, Val283, and Ala286 fosterhydrophobic interaction with the benzene ring and increase thestability of binding interaction. The phenolic hydroxyl group (C-7) of baicalein and the carbamoyl oxygen atom of Met 280residue form hydrogen bonding which stabilizes the complex.The C-7 hydroxy group was considered very essential forenhancing its inhibitory activity against tyrosinase.127–129

Jamshaid et al.87 reported compound 69 as a new syntheticanalog of avone with potential TIs (Table 8). It is obvious fromtheir ndings that the indole moiety present at the 2-position of

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the avonemotif is responsible for enhanced TI action as reectedby the greater activity obtained relative to the standard. Further-more, the other substituted synthetic 2-phenylchromonessubstituted with a nitro group at the 4th position and dimethoxygroups at 3rd and 4th positions on the B ring, respectively, showedextraordinary activity as compared to the standard kojic acid.

5.5 Flavanols

Flavanonols are a diverse subclass of the avonoid family thatincludes catechin monomers and epicatechin isomers, as wellas oligomeric and polymeric proanthocyanidins and condensedtannins. Flavanols found in the higher plants and medicinalherbs include epicatechin, catechin, epi-gallocatechin, ECG,EGCG, and proanthocyanidins. Astelia neocaledonica is a preva-lent Caledonia tree, which was recognized as an anti-tyrosinasesource due to the existence of gallocatechin and tannins.Furthermore, proanthocyanidins from Clausena lansiumshowed excellent TI in a competitive style and demonstratedgood melanogenic inhibition activity of B16 cells (Table 9).Another study described that compound 81, puried fromAnnona squamosa pericarp, could strongly inhibit the mono-phenolase and diphenolase actions of tyrosinase, competi-tively.130–133 Additionally, Kim et al.134 had shown that catechin–aldehyde poly-condensates reduce the hydroxylation of L-tyro-sine and oxidation of L-DOPA by chelation to the tyrosinaseactive site.

Many avanols have been extracted from plants, and severalhave been classied as potent TI's. The inhibitory mode of thesenatural inhibitors is normally competitive inhibition for theoxidation of L-dopa by tyrosinase where the 3-hydroxy-4-ketomoiety (Table 9) of the avanol structure plays the key role incopper chelation.28,135–138 Currently, to the best of our knowl-edge, there is no literature available on synthetic avanols asmushroom TIs inhibitors.

5.6 Isoavones

Isoavones like daidzein and genistein, as well as their glyco-sides, are oen found in medicinal plants. Park et al.





Table 8 Chemical structures of synthetic flavones and IC50 values obtained against mushroom tyrosinase

Compound no. Compound name Chemical structuresIC50 values(mM) Reference

65 5,7-Dibromo-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one 0.57 87

66 5,7-Dibromo-2-(4-nitrophenyl)-4H-chromen-4-one 0.27 87

67 5,7-Dibromo-2-(3,4-dimethoxyphenyl)-4H-chromen-4-one 0.49 87

68 5,7-Dibromo-2-(thiophen-2-yl)-4H-chromen-4-one 0.68 87

69 5,7-Dibromo-2-(1H-indol-3-yl)-4H-chromen-4-one 0.22 87

70 5,7-Dibromo-2-(naphthalen-1-yl)-4H-chromen-4-one 3.41 87

71 4-(5,7-Dibromo-4-oxo-4H-chromen-2-yl)benzoic acid 3.28 87


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Table 8 (Contd. )

Compound no. Compound name Chemical structuresIC50 values(mM) Reference

72 5,7-Dibromo-2-(3-nitrophenyl)-4H-chromen-4-one 3.28 87

73 5,7-Dibromo-2-(furan-2-yl)-4H-chromen-4-one 2.07 87

Standard Kojic acid 1.79 87

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investigated the activity of certain natural dihydroxylisoavoneanalogs with a variable –OH group position at the aryl ring ofisoavone isolated from Korean fermented soybean paste ininhibiting tyrosinase. They discovered two trihydroxyisoavoneanalogs with different positions of the hydroxyl groups. Theseproduced IC50 values of 5.23 (compound 92) and 11.2 mM(compound 93) against mushroom tyrosinase. However,compound 91, a related derivative, showed no anti-tyrosinaseactivity (Table 10). As a result, it has been suggested that theC6 and C7 –OH groups of the isoavone scaffold might besignicant for inhibiting tyrosinase.135

Likewise, compound 93 extracted from soygerm koji, wasevaluated by Chang et al. They also discovered that 7,8,40-tri-hydroxyisoavone is a potent inhibitor of tyrosinase mono-phenolase activity, with an IC50 value of 9.2 mM, rendering 93 sixtimes more active than kojic acid. This compound had anirreversible inhibitory effect on both monophenolase anddiphenolase activities. It may be concluded that the presence ofthe –OH group at both the C7 and C8 positions could entirelyalter the inhibitory effect of the isoavones from the reversiblecompetitive to the irreversible suicide form ref. 139 and 140.Recently, the two isoavones 6-hydroxydiadezein (compound96) and calycosin (compound 97), isolated from Agave ameri-cana were recognized as competitive inhibitors.141 The mostactive mushroom TI was compound 112, which was 5 to 9 timeshigher than arbutin. In the various test intervals, the onlyoxygenated isoavones at the C6 position displayed an excellentanti-tyrosinase activity with IC50 values of 52.3 and 45.8 mM (ref.142) (Table 10).

In the 7-oxygenated series (Table 10), compounds 107 and116 possessed notable anti-tyrosinase activity (IC50 ¼ 53.9 and38.1 mM), whereas the potent TI among the 7,8-dimethylatedseries was compound 118 (IC50 ¼ 45.8 mM). Noteworthy,

22180 | RSC Adv., 2021, 11, 22159–22198

isoavones having free hydroxyl groups at C6, C7, or C40 usuallyexhibited potent anti-tyrosinase activities. However, the activitybecomes erratic when both the C7and C40 are hydroxylated inthe same motif. For instance, while daidzein and genistein wereinactive, 6,40-dihydroxy-7,8-dimethylisoavone and 6-hydrox-ydaidzein were the most potent TIs. In this study, o-dihydroxy-lated series with –OH groups at C7 and C8 or C6 and C7appeared to be better mushroom TI's, except the C7-methoxylated derivatives. This result revealed that the inhibi-tory manner of the o-dihydroxylated series was different fromthat of the non-o-dihydroxylated series.46

Basically, O-bearing substituents at C40 of ring B seem tocontribute to the anti-tyrosinase activity, whereas the –OH or–MeO at C20 and C30 of ring B of an isoavone tend to attenuatethe TI effect. However, the existence of a lipophilic end inhydroxylated isoavones may contribute to the binding tomushroom tyrosinase.143 The synthetic analogs of isoavones asTIs have not yet been reported in the literature.

5.7 Flavanones

Flavanones may be discerned from other avonoids by theabsence of the covalent double bond ‘]’ connecting the 2nd and3rd positions of the pyrone ring. A systematic study about theinuence of the number and position of –OH groups on the arylring indicated the importance of p-position on ring B.144 Natu-rally occurring avanones such as streppogenin, bavachinin,alpinetin are primarily found in medicinal herbs and citrusfruits. Streppogenin, a copper chelator avanone, inhibitstyrosinase reversibly and competitively (Table 11).

Furthermore, docking ndings demonstrated that hesper-etin chelates a Cu2+ ion coordinating with three histidine(His61, His85, and His259) residues within the enzyme's active





Table 9 Chemical structures of natural flavanols and IC50 values obtained against mushroom tyrosinase

Compoundno. Compound name Chemical structures

IC50 values(mM) Reference

74 Dihydromyricetin 849.88 167

75 Taxifolin 0.24 118

76 Dihydromorin 9.4 10

77 Dihydroxykampherol >200 58

78 Broussoavonol J 9.29 96

79 3,5,7-Trihydroxy-2-(4-hydroxyphenyl)chroman-4-one 25 22

80 Chlorophorin 6.6 172


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Table 9 (Contd. )



81 Proanthocyanidins 55.01 146

824-(3,8-Diacetoxy-5-hydroxy-4-oxochroman-2-yl)-1,2-phenylene diacetate

>230 28

83 3,5,7-Trihydroxy-2-(4-hydroxyphenyl)chroman-4-one >100 28

842-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-3-methoxychroman-4-one

>300 28

854-(3,7-Diacetoxy-5-hydroxy-4-oxochroman-2-yl)-1,2-phenylene diacetate

>230 28

86 2-(2-Hydroxyphenyl)-3,5,7-trihydroxychroman-4-one 25 28


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Table 9 (Contd. )



872-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxychroman-4-one

>300 28

882-(3,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one

75.8 28

892-(3,4-Dihydroxyphenyl)-3,5-dihydroxy-(7,2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl)oxychroman-4-one

>200 28

903,5,7-Trihydroxy-2,7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydrobenzofuran-5-ylchroman-4-one

28.8 28

Standard Kojic acid 23728 and167

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site. Chiari et al.144 validated the TI activity of a substituted 6-iso-prenoid avanone isolated from Dacryopinax elegans in anotherreport. Among these inhibitors, streppogenin was a strongerinhibitor than the positive controls, arbutin or kojic acid.

Several phenolic compounds isolated from various plantswere tested as inhibitors of mushroom tyrosinase. The Mor-aceae family is an effective supplier of skin-whiteningagents4,145–152 (Table 11), and a source of several avanoneanalogs that display, in some cases, very low IC50 values. Likecompounds in the previous class, these analogs have not beenexplored as synthetic inhibitors against tyrosinase.


5.8 Flavonols

Plants contain numerous avonols, some of which have beendescribed as tyrosinase inhibitors. The avonol's structure, 3-hydroxy-4-keto moiety, is essential in copper chelation, andthe inhibitory mode of avonol inhibitors is normallycompetitive inhibition for the oxidation of L-dopa by tyrosi-nase.153 Kaempferol, myricetin, quercetin, isorhamnetin, gal-angin, morin, and their glycosides are the prevalent naturallyoccurring avonols, mostly found as O-glycosides.154–160 So far,several avonols such as quercetin from Olea europaea,kaempferol from Hypericum laricifolium, and Crocus sativus,

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Table 10 Chemical structures of natural isoflavones and IC50 values obtained against mushroom tyrosinase



91 Daidzein 17.50 30

92 7,30,40-Trihydroxyisoavone 52.3 135

93 7,8,40-Trihydroxyisoavone 11.21 135

94 3,8-Dihydroxy-9-methoxy pterocarpan 16.7 141

95 30-Hydroxygenistein 15.9 168

96 6-Hydroxydaidzein 0.009 58

97 Calycosin 1.45 180

98 Cajanin 67.9 58

99 Daidzein-7-O-b-glucopyranose 22.2 58


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Table 10 (Contd. )



100 5-Hydroxy-daidzein-7-O-b-glucopyranose 4.39 58

101 7-(b-Glucopyranosyl)-20-hydroxygenistein 729 58

102 (8,9)-Furanyl-pterocarpan-3-ol 7.18 50

103 Neorauavane 500 78

104 30-Hydroxy-8-methoxy vestitol 67.8 50

105 Khrinone B 54.0 50

1067,8-Dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one

45.8 48

1077,8-Dihydroxy-3-(3-methoxyphenyl)-4H-chromen-4-one

53.9 48


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Table 10 (Contd. )



1083-(3,4-Dihydroxyphenyl)-8-hydroxy-7-methyl-4H-chromen-4-one

129.9 48


96.4 48


50.9 48


82.8 48


8.1 68


15.6 68


171.1 68

115 7-Hydroxy-3-(3-hydroxyphenyl)-4H-chromen-4-one 110.9 68


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Table 10 (Contd. )



116 3-(4-Hydroxyphenyl)-7-methyl-4H-chromen-4-one 38.1 68


141.3 68

1186-Hydroxy-3-(4-hydroxyphenyl)-7,8-dimethyl-4H-chromen-4-one

45.8 68

1196-Hydroxy-3-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one

83.5 68

Standard Kojic acid 8948, 68, 135and 141

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quercetin-40-O-beta-D-glucoside from Parornix bifurca, quer-cetin glucopyranoside and kaempferol glucopyranoside frommulberry leaves, morin and 2,3-cis-dihydromorin, 2,3-trans-dihydromorin from Chloropsis cochinchinensis, were found toact as tyrosinase inhibitors (Table 12). Moreover, it was re-ported that three 3-hydroxyavones including kaempferol,galangin, and quercetin inhibit the L-DOPA oxidation processcatalyzed by tyrosinase, and apparently, this TI activity arisesfrom their Cu2+ chelating ability.161–166 Kubo et al. assumedthat the chelation mechanism by avonols may be attributedto the free 3-OH group. Remarkably, quercetin acts asa cofactor and does not inhibit monophenolase activity. Thecommon feature of these three avonols167–172 is that they allinhibit diphenolase activity by chelating copper in the enzyme.Furthermore, quercetin glucoside, with an IC50 value of 1.9mM, inhibited tyrosinase more effectively than the positivestandard, kojic acid.173–178

Jamshaid et al.,85 synthesized some 3-hydroxyavonederivatives and tested their TI potential against mushroomtyrosinase (Table 13). Fascinatingly, the test analogs 2-(3-


(triuoromethyl)phenyl)-3-hydroxyavone (IC50 ¼ 0.280 mM)and 2-(4-chlorophenyl)-3-hydroxyavone (IC50 ¼ 0.230 mM)were found to be the most potent among all the synthesizedderivatives and superior to the positive control kojic acid.The 2-(3-(triuoromethyl)phenyl)-3-hydroxyavone possessesa highly electron-withdrawing group (–CF3) at the m-positionon ring B. This reveals that the structure ts nicely andstrongly interacts with the active site of the envisionedenzyme. Interestingly, 2-(2-(triuoromethyl)phenyl)-3-hydroxyavone (IC50 ¼ 0.30 mM), having triuoromethylgroup (–CF3) at the o-position of ring B, was found compar-atively less active than its m-isomer, but still more active thanthe standard.

Jamshaid et al.,87 synthesized substituted avonols where themost active derivative, which contains a strong EWG (–NO2) atthe p-position of the B ring, was 2-(4-nitrophenyl)-3-hydroxyavone (IC50 ¼ 0.284 mM). Likewise, the replacementof the aromatic B ring with other 5-membered heterocyclic ringssuch as thiophene (IC50 ¼ 0.347 mM) also produced excellentactivity. The TI by 2-(thiophen-3-yl)-3-hydroxyavone depends

RSC Adv., 2021, 11, 22159–22198 | 22187




Table 11 Chemical structures of natural flavanones and IC50 values obtained against mushroom tyrosinase



120 5,50,7-Trihydroxy-20,40-dimethoxy-6-methylavanone 44.74 68

121 Streppogenin 1.3 68

1225,7,20-Trihydroxy-50-(1000,1000-dimethylallyl)-8-prenylavanone

27.5 97

123 Liquiritigenin 22.0 50

124 Bavachinin 143.9 30

125 Corylifolin 23.6 30

126 Alpinetin 450 50


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Table 11 (Contd. )



127 Delanin 0.26 144

128 5,7,20-Trihydroxy-8,30-diprenylavanone 68.5 97

1295,7,20-Trihydroxy-5'-(1000,1000-dimethylallyl)-8-prenylavanone

27.5 142

130 2-(2,4-Dihydroxyphenyl)-7-hydroxychroman-4-one 0.11 4

1315,7-Dihydroxy-2-(4-hydroxyphenyl)-6-(3-methylbut-2-en-1-yl)chroman-4-one

38.1 4

1325,7-Dihydroxy-2-(2-hydroxy-4,6-dimethoxy phenyl)-6-methylchroman-4-one

44.74 4


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Table 11 (Contd. )



1337-Hydroxy-2-(4-hydroxyphenyl)-5-methoxy-8-(3-methylbut-2-en-1-yl)chroman-4-one

77.4 4

1342-(2,4-Dihydroxyphenyl)-5-hydroxy-7-methoxychroman-4-one

2.0 4

135 2-(2,4-Dihydroxyphenyl)-5,7-dihydroxychroman-4-one 1.76 4

136 5,7-Dihydroxy-2-(4-hydroxy phenyl)chroman-4-one >300 4

137(3,4-Dihydroxy-4-(hydroxymethyl)tetrahydrofuran-2-yl)oxy-(4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxyphenyl-7-hydroxychroman-4-one

88.91 4

138 5,7-Dihydroxy-2-phenyl chroman-4-one >500 4

Standard Kojic acid 3104, 30 and50


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Table 12 Chemical structures of natural flavonols and IC50 values obtained against mushroom tyrosinase



139 Quercitin 10.73 58

140 Kaempferol 5.5 71

141 Galangin 3.55 38

142 Rutin 130 101

1432-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one

53.4 31

1442-(3,4-Dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chromen-4-one1

72.5 31

145 6-Hydroxykaempferol 124 31


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Table 12 (Contd. )



146 6-Hydroxygalangin 182 31

Standard Kojic acid 31831, 38, 58and 71

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on the ability of a ‘S’ atom to coordinate with the dinuclear Cu2+

in the enzyme's active site. The high inhibitory potential may bedue to the electronegativity of the two –OCH3 groups at o- and p-positions of the B-ring which ts appropriately in the activepocket of the target enzyme. Moreover, the 5,7-dibromo-2-(4-chlorophenyl)-3-hydroxyavone has an EWD (–Cl) at 4th posi-tion on ring B. Perhaps, this functionality and its location havesuitable interactions with the enzyme's active site. Subse-quently, the next most active derivative, which contains a strongEWG (–NO2) at the 3rd position on the B ring, is 5,7-dibromo-2-(3-nitrophenyl)-3-hydroxyavone. Excitingly, the p-NO2

substituted 5,7-dibromo-3-hydroxyavone displayed enhancedactivity as compared to its m-analog (Table 13).

6. Conclusions and perspectives

Pigment disorders are triggered by the upregulation ordownregulation of tyrosinase. Because of the cosmeticallysignicant issue of abnormal pigmentation and its impact onthe quality of life and the development of life-threateningdiseases, there is a great demand for melanogenesis inhibi-tors. The regulation of melanogenesis is a complicatedprocess which involves several cellular factors. Tyrosinase,the central culprit in the enzymatic pathway of melanogen-esis, has emerged as the most important target for thetreatment of clinical and aesthetic hyperpigmentation. Theenzyme catalyzes the rst and only rate-limiting step inmelanogenesis. Plants have always played a signicant roleas supply for drug lead compounds. In particular, someplants are rich in polyphenols, which form building blocksfor the biosynthesis of chalcone, avones, and avonols,among others, which further form proanthocyanins andfunction as antioxidants. However, as these phytoconstituenthave poor solubility and stability when formulated indifferent matrices, their bioavailability becomes a majorconcern. Pleasingly, their synthetic structural analogs offerinteresting anti-tyrosinase activities, and thus help in the

22192 | RSC Adv., 2021, 11, 22159–22198

development of customized chemical agents with desiredfeatures to maximize inhibitory activity, stability, and safetyfor long-term use in skincare. Consequently, in recent years,many inhibitors have been identied and shown to actagainst tyrosinase.

It is fascinating to note that, regardless of the variety ofnatural inhibitors, many TI's are phenolic in nature. Severalinvestigators had considered suitable skeletons based onnatural compound structures and created new syntheticinhibitors. Among all the natural and synthetic avonoidderivatives, the preceding survey of tabulated compounds andtheir inhibitory results suggest that the avonol moiety canserve as an effective scaffold and a lead structural feature andfoundation for the further development of novel tyrosinaseinhibitors. For avonols (3-hydroxyavones), vicinal positionsof the hydroxyl group and keto functionality play a signicantrole in chelating with Cu2+ ions to render them the most potentanti-tyrosinase agents.

Useful provisions have been proposed by molecularmodeling studies that outline the essential structural elementsrequired for the manifestation of inhibitory actions of naturalcompounds, providing a guide for the design of more efficientsynthetic bioinspired chemical repressors. Hence, it is impor-tant to assess the efficiency and safety of inhibitors by exam-ining e.g., whether the candidate inhibitor is a tyrosinasesubstrate being altered on exposure to the enzyme. Futureresearch guidelines on pigmentation regulation by tyrosinasemodulation also include the production of highly specicassays of enzymatic activity, as well as the proper use of novelformulations to enhance the efficiency of the inhibitors byincreasing their bioavailability. In conclusion, we expect thatthis review will serve as helpful reference to the medicinalchemists working on melanogenesis, specically on varioustyrosinase enzymes, to develop lead tyrosinase inhibitors withdrug-like characteristics.





Table 13 Chemical structures of synthetic flavonols and IC50 values obtained against mushroom tyrosinase



147 5,7-Dibromo-2-(4-chlorophenyl)-3-hydroxy-4H-chromen-4-one 0.71 87

148 5,7-Dibromo-3-hydroxy-2-(3-nitrophenyl)-4H-chromen-4-one 0.15 87

149 5,7-Dibromo-2-(4-uorophenyl)-3-hydroxy-4H-chromen-4-one 2.36 87

1505,7-Dibromo-2-(4-(dimethylamino)phenyl)-3-hydroxy-4H-chromen-4-one

0.50 87

151 5,7-Dibromo-3-hydroxy-2-(naphthalen-1-yl)-4H-chromen-4-one 0.564 87

152 5,7-Dibromo-3-hydroxy-2-(p-tolyl)-4H-chromen-4-one 0.126 87

153 3-Hydroxy-2-(thiophen-2-yl)-4H-chromen-4-one 0.347 85


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Table 13 (Contd. )



154 3-Hydroxy-2-(4-nitrophenyl)-4H-chromen-4-one 0.284 85

1555,7-Dibromo-2-(3,4-dimethoxyphenyl)-3-hydroxy-4H-chromen-4-one

0.093 87

156 2-(4-Fluorophenyl)-3-hydroxy-4H-chromen-4-one 0.799 85

157 3-Hydroxy-2-(2-(triuoromethyl) phenyl)-4H-chromen-4-one 0.30 85

158 2-(4-Chlorophenyl)-3-hydroxy-4H-chromen-4-one 0.230 85

Standard Kojic acid 1.79 85 and 87

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Abbreviations

DOPA

22194 | R

Dihydroxyphenylalanine;
TI's Tyrosinase Inhibitors PTU 1-Phenyl-2-thiourea UV Ultraviolet kDa Kilo dalton Em Met-tyrosinase
SC Adv., 2021, 11, 22159–22198

Eox

© 202

Oxy-tyrosinase
IC50 Half maximal inhibitory concentration IR Infrared HOPNO 2-Hydroxypyridine N-oxide TMBC 2,4,20,40-Tetrahydroxy-3-(3-methyl-2-butenyl) chalcone His Histamine Val Valine Phe Phenylalanine Met Methionine
1 The Author(s). Published by the Royal Society of Chemistry




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Ser

© 2021 Th

Serine
Ala Alanine ECG Epicatechin gallate EGCG Epigallocatechin gallate EWG Electron-withdrawing group
Conflicts of interest

Hereby, I declare that we have no conicts of interest.

Acknowledgements

The authors would like to thank the Deanship of ScienticResearch at Umm Al-Qura University for supporting this workunder grant number 18-SCI-1-02-0006. The authors are alsograteful to the Higher Education Commission of Pakistan (HEC)for providing nancial assistance under the Project No. (NRPU-6484).

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